JP2016525881A - 改変キメラ抗原受容体(car)t細胞のヒト応用 - Google Patents
改変キメラ抗原受容体(car)t細胞のヒト応用 Download PDFInfo
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Abstract
Description
配列表の組み込み
遺伝子治療を免疫療法と組み合わせることで臨床等級T細胞の効力を改善し、(i)腫瘍関連抗原(TAA)の認識に優れた可能性、(ii)注入後の持続性、(iii)腫瘍部位に移動する可能性、及び(iv)腫瘍微小環境内のエフェクター機能を再循環させる能力を持つ生物学的製剤を遺伝子操作することができる。遺伝子治療と免疫療法とのそのような併用により、B系統抗原に対するT細胞の特異性を再指向することができ、B細胞悪性腫瘍が進行した患者は、そのような腫瘍特異的T細胞の注入から恩恵を受ける(Jenaら、2010;Tillら、2008;Porterら、2011;Brentjensら、2011;Cooper及びBollard、2012;Kalosら、2011;Kochenderferら、2010;Kochenderferら、2012;Brentjensら、2013)。ヒト応用に設計されたT細胞の遺伝子操作のほとんどのアプローチは、キメラ抗原受容体(CAR)の安定発現用のレトロウイルス及びレンチウイルスを使用してきた(Jenaら、2010;Ertlら、2011;Kohnら、2011)。このアプローチは、現行の医薬品製造管理及び品質管理基準(cGMP)に準拠しているが、限られた数の生産施設からの臨床等級組み換えウイルスの生産及びリリースに依存しているため高価になり得る。血液悪性腫瘍及び固形腫瘍に対して特異性を持つ遺伝子組み換えされた臨床等級T細胞製品を生成するための新しい方法が必要である。
I.定義
II.キメラ抗原受容体
III.実施形態に関する方法及び組成物
IV.例示のヒトCD19特異的キメラ抗原受容体T細胞
V.例示のHERV標的キメラ抗原受容体T細胞
VI.最小残存疾患を標的にするためのキメラ抗原受容体T細胞を共発現する例示の膜結合IL−15
VII.免疫系及び免疫療法
VIII.人工抗原提示細胞
IX.本発明のキット
下記の実施例は、本発明の好ましい実施形態を実証するために含められる。下記の実施例において開示される技術は、本発明の実施において十分に機能することが本発明者によって発見された技術を表しているため、その実施のための好ましい態様を構成すると見なされ得ることが当業者によって理解されるはずである。しかしながら、当業者は本開示に照らして、多くの変化が、開示される具体的な実施形態において行われ得ること、そして、多くの変化により、同様な結果または類似する結果が依然として、本発明の精神および範囲から逸脱することなく得られ得ることを理解しなければならない。
実施例1−末梢血及び臍帯血からのT細胞を遺伝的に改変するためのスリーピングビューティ及び人工抗原提示細胞の臨床応用−材料及び方法
実施例2−末梢血及び臍帯血からT細胞を遺伝的に改変するためのスリーピングビューティ及び人工抗原提示細胞の臨床応用−結果
実施例3−スリーピングビューティ及び人工抗原提示細胞を用いて、キメラ抗原受容体を安定的に発現する臨床等級CD19特異的T細胞の製造−材料及び方法
表4:フローサイトメトリーに用いた抗体。
RTL=((プローブ有りの平均FL1試料細胞−プローブ無しの平均FL1試料細胞)×2×100)/(プローブ有りの平均FL1参照細胞−プローブ無しの平均FL1参照細胞)
(実験的51Cr放出−自発的51Cr放出)/(最大51Cr放出−自発的51Cr放出)×100
自発的放出及び最大放出は、CMまたは0.1%トリトンX−100(Sigma)でそれぞれインキュベートされた標的細胞からの馴化上清中のクロムを測定することにより判断した。
実施例4−スリーピングビューティ及び人工抗原提示細胞を用いて、キメラ抗原受容体を安定的に発現する臨床等級CD19特異的T細胞の製造−結果
表5:K562 aAPC(クローン#4)のSTRフィンガープリンティング
表6:電気穿孔し増殖させたT細胞を放出するための合否判定基準
表8:遺伝子改変T細胞による自律的な細胞増殖の欠如。
aT細胞を播種した場合の培養日数
b実験の開始時に培養で播種した全T細胞数
cサイトカイン及びaAPC不在下で計数した全T細胞数
dサイトカイン及びaAPC(陽性対照)の存在下で計数した全T細胞(推定)数
e倍数変化率=[(c/b)÷(d/b)]*100
表9:電気穿孔し増殖させたT細胞の処理中試験
実施例5−キメラ抗原受容体を発現するように遺伝子操作された養子T細胞を用いた、がん及び感染に発現した古代レトロウイルスの標的化−方法
51Cr放出%=(実験的放出−バックグラウンド放出)/(最大放出−バックグラウンド放出)×100
実施例6−キメラ抗原受容体を発現するように遺伝子操作された養子T細胞を用いた、がん及び感染を発現した古代レトロウイルスの標的化−結果
実施例7−微小残存病変の免疫療法で使用される可能性のあるin vivoで長寿命のT細胞を生成するための膜結合型サイトカインの使用
実施例8−SBトランスポゼースをコードするmRNAを用いて最小限に操作されたT細胞の生成
参考文献
以下の参考文献が、本明細書の説明を補助する典型的な手続に関するまた他の詳細を与える限りにおいて、参照することにより本明細書に明確に取り込まれている。
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Claims (104)
- in vitro方法であって、
(a)細胞の試料を対象から得ることと、ここで、前記試料は、T細胞またはT前駆細胞を含む;
(b)前記細胞を、トランスポゾンフランクキメラ抗原受容体(CAR)をコードするDNAと前記CARをコードする前記DNAを前記細胞のゲノム中に組み込むのに有効なトランスポゼースとでトランスフェクトし、トランスジェニックCAR発現T細胞の集団を提供することと;
(c)必要に応じて、CAR発現T細胞の増殖を選択的に高める培地中で前記トランスジェニックCAR細胞の集団をex vivoにて培養することと、ここで、前記トランスジェニックCAR T細胞は培養され、仮にそうであったとしても、18日以下である、
を含む、前記方法。 - in vitro方法であって、
(a)細胞の試料を対象から得ることと、ここで、前記試料は、T細胞またはT前駆細胞を含み、前記対象から得た際に、約20〜200mlの初期容量を有する;
(b)前記細胞を、トランスポゾンフランクキメラ抗原受容体(CAR)をコードするDNAと前記CARをコードする前記DNAを前記細胞のゲノム中に組み込むのに有効なトランスポゼースとでトランスフェクトし、トランスジェニックCAR発現T細胞の集団を提供することと;
(c)必要に応じて、CAR発現T細胞の増殖を選択的に高める培地中で前記トランスジェニックCAR細胞の集団をex vivoにて培養することと
を含む、前記方法。 - 工程(b)前に前記試料中のT細胞を精製または濃縮することをさらに含む請求項1または2に記載の方法。
- 前記試料中のT細胞を濃縮することが、単核球分画を回収することを含む請求項3に記載の方法。
- 前記トランスジェニックCAR T細胞が、14日以下で培養される請求項1または2に記載の方法。
- 工程(a)乃至(c)のプロセスが、18日以下で完了する請求項1または2に記載の方法。
- 前記細胞試料が、前記対象から得た際に、約20〜200mlの初期容量を有する請求項1に記載の方法。
- 前記細胞試料が、前記対象から得た際に、約50〜200ml、50〜100ml、または100〜200mlの初期容量を有する請求項2または7に記載の方法。
- 前記細胞試料が、凍結保存試料である請求項1または2に記載の方法。
- 前記細胞試料が、臍帯血由来である請求項1または2に記載の方法。
- 前記細胞試料が、前記対象からの末梢血液試料である請求項1または2に記載の方法。
- 前記細胞試料をアフェレーシスにより得た請求項1または2に記載の方法。
- 前記細胞試料を静脈穿刺により得た請求項1または2に記載の方法。
- 前記細胞試料が、T細胞の亜集団である請求項1または2に記載の方法。
- 前記トランスジェニックCAR細胞が、内因性T細胞受容体及び/または内因性HLAを発現するために不活性化される請求項1または2に記載の方法。
- 前記細胞試料を得ることが、前記細胞を第三者から得ることを含む請求項1または2に記載の方法。
- 工程(b)において、CARをコードするDNAを前記T細胞にエレクトロポレートすることを含む請求項1または2に記載の方法。
- 工程(b)において、前記細胞をウイルスに感染または該ウイルスで形質導入することを伴わない請求項1または2に記載の方法。
- 前記細胞をトランスフェクトすることが、膜結合型Cγサイトカインをコードする核酸で前記細胞をトランスフェクトすることをさらに含む請求項1または2に記載の方法。
- 前記膜結合型Cγサイトカインが、膜結合型のIL−7、IL−15、またはIL−21である請求項19に記載の方法。
- 前記膜結合型Cγサイトカインが、IL−15−IL−15Rα融合タンパク質である請求項19に記載の方法。
- CARをコードする前記DNAが、プラスミドである請求項1または2に記載の方法。
- 前記トランスポゼースが、DNA発現ベクターとして提供される請求項1または2に記載の方法。
- 前記トランスポゼースが、mRNAとして提供される請求項1または2に記載の方法。
- 前記mRNAが、キャップド及び/またはポリA尾部を含む請求項24に記載の方法。
- 前記トランスポゼースが、ポリペプチドまたは発現可能RNAとして提供される請求項1または2に記載の方法。
- 前記トランスポゼースが、サケ科型Tc1様トランスポゼース(SB)である請求項1または2に記載の方法。
- 前記トランスポゼースが、SB11またはSB100xトランスポゼースである請求項27に記載の方法。
- 前記トランスジェニックCAR細胞を培養すること(c)が、前記CAR発現T細胞の増殖を刺激する樹状細胞または人工抗原提示細胞(aAPC)の存在下で前記トランスジェニックCAR細胞を培養することを含み得る請求項1または2に記載の方法。
- 前記aAPCが、トランスジェニックK562細胞である請求項29に記載の方法。
- 前記aAPCが、(i)前記トランスジェニックCAR細胞上で発現した前記CARにより標的とされる抗原;(ii)CD64;(ii)CD86;(iii)CD137L;及び/または(v)前記aAPCの表面上で発現した膜結合型IL−15を含む請求項29に記載の方法。
- 前記aAPCが、前記aAPCの表面上で発現したCAR結合抗体またはその断片を含む請求項29に記載の方法。
- 前記aAPCが、T細胞を活性化または共刺激する付加分子を含む請求項29に記載の方法。
- 前記付加分子が、膜結合型Cγサイトカインを含む請求項33に記載の方法。
- 前記aAPCが不活性化される請求項29に記載の方法。
- 前記aAPCが照射される請求項35に記載の方法。
- 前記aAPCが、感染性物質について試験し、該感染性物質を含まないことが確認された請求項29に記載の方法。
- aAPCの存在下で前記トランスジェニックCAR細胞を培養することが、IL−21及び/またはIL−2を含む培地中で前記トランスジェニックCAR細胞を培養することを含む請求項29に記載の方法。
- aAPCの存在下で前記トランスジェニックCAR細胞を培養することが、約10:1〜約1:10(aAPCに対するCAR細胞)の比率で前記細胞を培養することを含む請求項29に記載の方法。
- 前記トランスジェニック細胞を培養すること(c)が、7、14、21、28、35、または42日以下である請求項1または2に記載の方法。
- 前記トランスジェニック細胞を培養すること(c)が、前記トランスジェニックCAR細胞の集団の1倍加未満をもたらす請求項1または2に記載の方法。
- 前記トランスジェニック細胞を培養すること(c)が、前記トランスジェニックCAR細胞の集団の少なくとも1倍加をもたらす請求項1または2に記載の方法。
- 前記トランスジェニック細胞が、aAPCの存在下でex vivo培養されない請求項1または2に記載の方法。
- 工程(b)または工程(c)の後にCAR発現T細胞の前記細胞集団を濃縮することをさらに含む請求項1または2に記載の方法。
- 前記濃縮することが、蛍光活性化細胞選別(FACS)を含む請求項44に記載の方法。
- 前記濃縮することが、CAR発現細胞を選別することを含む請求項45に記載の方法。
- 前記濃縮することが、常磁性粒子上でCAR発現細胞を選別することを含む請求項46に記載の方法。
- CAR発現細胞を選別することが、CAR結合抗体の使用を含む請求項46に記載の方法。
- 前記濃縮することが、CD56+細胞の枯渇を含む請求項44に記載の方法。
- 前記トランスジェニックCAR細胞の集団の試料を凍結保存することをさらに含む請求項1または2に記載の方法。
- 前記CARが、がん細胞抗原を標的にする請求項1または2に記載の方法。
- 前記がん細胞抗原が、CD19、CD20、ROR1、CD22がん胎児性抗原、アルファフェトプロテイン、CA−125、5T4、MUC−1、上皮腫瘍抗原、前立腺特異抗原、メラノーマ関連抗原、変異p53、変異ras、HER2/Neu、葉酸結合タンパク質、HIV−1エンベロープ糖タンパク質gp120、HIV−1エンベロープ糖タンパク質gp41、GD2、CD123、CD33、CD138、CD23、CD30、CD56、c−Met、メソテリン、GD3、HERV−K、IL−11Rα、κ鎖、λ鎖、CSPG4、ERBB2、EGFRvIII、VEGFR2、HER2−HER3の組み合わせ、またはHER1−HER2の組み合わせである請求項51に記載の方法。
- 前記がん細胞抗原が、CD19であり、前記CARが、CD19標的CARである請求項52に記載の方法。
- 前記CARが、配列番号1に少なくとも90%同一であるアミノ酸配列を含むCD19標的CARである請求項53に記載の方法。
- 前記CARが、HERV−Kエンベロープタンパク質標的CARである請求項52に記載の方法。
- 前記CARが、モノクローナル抗体6H5のscFv配列を含む請求項55に記載の方法。
- 前記CARが、病原体抗原を標的にする請求項1または2に記載の方法。
- 前記病原体が、真菌病原体、ウイルス性病原体、または細菌性病原体である請求項57に記載の方法。
- 前記病原体が、マラリア原虫、トリパノソーマ、アスペルギルス、カンジダ、HSV、RSV、EBV、CMV、JCウイルス、BKウイルス、またはエボラ病原体である請求項57に記載の方法。
- 請求項1または2に記載の方法により作製されたT細胞組成物。
- 疾患を有するヒト対象においてT細胞応答をもたらす請求項60に記載の組成物。
- 前記疾患が、細胞増殖性疾患である請求項61に記載の組成物。
- 前記細胞増殖性疾患が、自己免疫疾患であり、前記CARが、前記自己免疫細胞を標的にする請求項61に記載の組成物。
- 前記細胞増殖性疾患が、がんであり、前記CARが、がん細胞抗原を標的にする請求項62に記載の組成物。
- 前記対象が、以前に抗がん治療を経験している請求項61に記載の組成物。
- 前記対象が、寛解期であるかまたは、前記対象が、前記がんの症状がないが、検出可能ながん細胞を含む請求項61に記載の組成物。
- 前記疾患が、病原体により引き起こされる感染性疾患であり、前記CARが、病原体抗原を標的にする請求項61に記載の組成物。
- HERV−Kのエンベロープタンパク質を標的にする発現キメラT細胞受容体(CAR)を含む単離トランスジェニック細胞。
- 前記細胞が、ヒト細胞である請求項68に記載の単離細胞。
- 前記CARをコードするDNAを、前記細胞のゲノム中に組み込む請求項68に記載の単離細胞。
- 前記CARが、配列番号4に少なくとも90%同一であるアミノ酸配列を含む請求項68に記載の単離細胞。
- 前記CARをコードするDNAが、トランスポゾン反復配列によりフランクされる請求項68に記載の単離細胞。
- 配列番号5に少なくとも約90%同一である組み込みDNA配列を含む請求項68に記載の単離細胞。
- 前記CARが、モノクローナル抗体6H5のCDR配列を含む請求項68に記載の単離細胞。
- 前記CARが、モノクローナル抗体6H5のscFv配列を含む請求項73に記載の単離細胞。
- 前記CARが、配列番号4のアミノ酸配列を含む請求項73に記載の単離細胞。
- 前記対象に請求項68に記載のトランスジェニック細胞の有効量を投与することを含む、疾患を有するヒト対象においてT細胞応答をもたらす方法。
- 発現キメラT細胞受容体(CAR)及び発現膜結合型IL−15を含む単離トランスジェニック細胞であって、
前記膜結合型IL−15が、IL−15とIL−15Rαとの間の融合タンパク質を含む、前記単離トランスジェニック細胞。 - 前記細胞が、ヒト細胞である請求項78に記載の単離細胞。
- 前記膜結合型IL−15が、配列番号6に少なくとも90%同一であるアミノ酸配列を含む請求項78に記載の単離細胞。
- 前記膜結合型IL−15が、配列番号6のアミノ酸配列を含む請求項80に記載の単離細胞。
- 配列番号7に少なくとも90%同一であるポリヌクレオチド配列を含む請求項78に記載の単離細胞。
- 配列番号7のポリヌクレオチド配列を含む請求項82に記載の単離細胞。
- 前記CARをコードするDNAを、前記細胞のゲノム中に組み込む請求項78に記載の単離細胞。
- 前記膜結合型IL−15をコードするDNAが、染色体外要素を含む請求項78に記載の単離細胞。
- 前記膜結合型IL−15をコードするDNAを、前記細胞のゲノム中に組み込む請求項78に記載の単離細胞。
- 前記対象に請求項78に記載のトランスジェニック細胞の有効量を投与することを含む、疾患を有するヒト対象においてT細胞応答をもたらす方法。
- 前記疾患が、がんであり、前記CARが、がん細胞抗原を標的にする請求項87に記載の方法。
- 前記対象が、以前に抗がん治療を経験している請求項88に記載の方法。
- 前記対象が、寛解期である請求項89に記載の方法。
- 前記対象が、前記がんの症状がないが、検出可能ながん細胞を含む請求項89に記載の方法。
- 配列番号1;配列番号4、または配列番号6に少なくとも90%同一であるアミノ酸配列を含む組み換えポリペプチド。
- 配列番号1に少なくとも90%同一であるアミノ酸配列を含むCD19標的CARを含む請求項92に記載のポリペプチド。
- 配列番号1のアミノ酸配列を含む請求項93に記載のポリペプチド。
- 配列番号4に少なくとも90%同一であるアミノ酸配列を含むHERV−K標的CARを含む請求項92に記載のポリペプチド。
- 配列番号4のアミノ酸配列を含む請求項95に記載のポリペプチド。
- 配列番号6に少なくとも90%同一であるアミノ酸配列を含む膜結合型IL−15を含む請求項92に記載のポリペプチド。
- 配列番号6のアミノ酸配列を含む請求項97に記載のポリペプチド。
- 配列番号1;配列番号4、または配列番号6に少なくとも90%同一であるポリペプチドをコードするポリヌクレオチド。
- 配列番号2;配列番号3;配列番号5、または配列番号7に少なくとも90%同一である配列を含む請求項99に記載のポリヌクレオチド。
- 請求項92〜98に記載のポリペプチドまたは請求項99〜100に記載のポリヌクレオチドを含む宿主細胞。
- 前記細胞が、T細胞、T前駆細胞、またはaAPCである請求項101に記載の宿主細胞。
- 疾患を有するヒト対象においてT細胞応答をもたらす方法であって、
(a)前記対象から細胞の試料を得ることと、ここで、前記試料は、T細胞またはT前駆細胞を含む;
(b)前記細胞を、トランスポゾンフランクキメラ抗原受容体(CAR)をコードするDNAと前記CARをコードする前記DNAを前記細胞のゲノム中に組み込むのに有効なトランスポゼースとでトランスフェクトし、トランスジェニックCAR発現T細胞の集団を提供することと;
(c)必要に応じて、CAR発現T細胞の増殖を選択的に高める培地中で前記トランスジェニックCAR細胞の集団をex vivoにて培養することと、ここで、前記トランスジェニックCAR T細胞は培養され、仮にそうであったとしても、18日以下である;
(d)T細胞応答をもたらすために、前記対象に前記トランスジェニックCAR T細胞の有効量を投与することと
を含む、前記方法。 - 疾患を有するヒト対象においてT細胞応答をもたらす方法であって、
(a)前記対象から細胞の試料を得ることと、ここで、前記試料は、T細胞またはT前駆細胞を含み、前記対象から得た際に、約20〜200mlの初期容量を有する;
(b)前記細胞を、トランスポゾンフランクキメラ抗原受容体(CAR)をコードするDNAと前記CARをコードする前記DNAを前記細胞のゲノム中に組み込むのに有効なトランスポゼースとでトランスフェクトし、トランスジェニックCAR発現T細胞の集団を提供することと;
(c)必要に応じて、CAR発現T細胞の増殖を選択的に高める培地中で前記トランスジェニックCAR細胞の集団をex vivoにて培養することと;
(d)T細胞応答をもたらすために、前記対象に前記トランスジェニックCAR T細胞の有効量を投与することと
を含む、前記方法。
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